Atrial fibrillation (AF) is the most common sustained arrhythmia, reaching epidemic proportions in the aging U.S. population and resulting in significant morbidity, mortality, and socioeconomic burden. Preliminary studies indicate that idiopathic or lone AF is familial in at least 15% of patients, highlighting the importance of genetic factors in the pathogenesis of this disorder. The overall objective of this study is to identify genes for AF by linkage and mutational analyses. The first aim is to determine the chromosomal location of AF genes by genome-wide linkage analyses. Mapping studies will be carried out in 4 large families with autosomal dominant AF in which linkage to known loci for AF have been excluded. The second aim is to identify mutations in candidate genes for AF based on chromosomal location, cardiac expression, and physiological rationale. Novel genes, once identified, will be screened for additional inherited and de novo mutations in a cohort of 154 unrelated patients with familial and sporadic AF. The third aim is to determine the frequency and spectrum of heritable ion channel and nuclear membrane defects in racially-diverse cohorts with lone AF. The long-term objectives of this work are to gain new insights into molecular mechanisms of arrhythmogenesis and to improve prediction, prevention, and treatment of AF.